Calcium and Parkinson's disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Its causes are poorly understood and there is no proven therapeutic strategy for slowing disease progression. The core motor symptoms of PD are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). In these neurons, Ca2+entry through plasma membrane Cav1 channels drives a sustained feed-forward stimulation of mitochondrial oxidative phosphorylation. Although this design helps prevent bioenergetic failure when activity needs to be sustained, it leads to basal mitochondrial oxidant stress. Over decades, this basal oxidant stress could compromise mitochondrial function and increase mitophagy, resulting in increased vulnerability to other proteostatic stressors, like elevated alpha synuclein expression. Because this feedforward mechanism is no longer demanded by our lifestyle, it could be dispensed with. Indeed, use of dihydropyridines – negative allosteric modulators of Cav1 Ca2+ channels – comes with little or no effect on brain function but is associated with decreased risk and progression of PD. An ongoing, NIH sponsored, Phase 3 clinical trial in North America is testing the ability of one member of the dihydropyridine class (isradipine) to slow PD progression in early stage patients. The review summarizes the rationale for the trial and outlines some unanswered questions.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Oxidative damage, dysregulated neuronal Ca 2+ homeostasis, impaired DNA repair, impaired adaptive cellular stress responses, aberrant neuronal network activity, and neuroinflammation all occur in affected brain regions during the course of PD, and each of these age-related alterations increases the vulnerability of neurons to α-synuclein pathology, and mitochondrial and autophagy dysfunction (Olanow et al, 2015; Ransohoff, 2016; Sepe et al, 2016; Jahanshahi and Rothwell, 2017; Menzies et al, 2017; Surmeier et al, 2017a). Conversely, aggregating α-synuclein and mitochondrial dysfunction exacerbate oxidative stress and DNA damage, destabilize neuronal Ca 2+ homeostasis, and promote neuroinflammation (Schapira et al, 2014).…”

Calcium Channel Antagonists as Disease-Modifying Therapy for Parkinson’s Disease: Therapeutic Rationale and Current Status

“…32,33,34 Consequently, blocking CaV1.3 channels should provide a reduction in oxidative stress in surviving neurons (and hence provide neuroprotection) but should not affect their autonomous activity and physiological function (Fig. 1).…”

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

“…They also have long unmyelinated axons and extensive arborization making their energy demands higher than most neurons [76]. To maintain basal DA tone across the expansive region of their innervation, they fire tonically with pacemaker activity driven by L-type calcium channels [77]. These channels are associated with higher ROS production, greater mitochondrial dysfunction, increased energy demand, and heightened vulnerability to PD-related toxins [77-79].…”

“…To maintain basal DA tone across the expansive region of their innervation, they fire tonically with pacemaker activity driven by L-type calcium channels [77]. These channels are associated with higher ROS production, greater mitochondrial dysfunction, increased energy demand, and heightened vulnerability to PD-related toxins [77-79]. These features make SNc DA neurons particularly vulnerable to compromised bioenergetic status and may explain their relatively selective degeneration in PD [80-83].…”

“…As a byproduct of OXPHOS, mitochondria also produce ROS that over time can damage mitochondria and impair their function [77]. This decreases cellular energy production and can result in chronic ROS overproduction, creating a cycle of increasing mitochondrial dysfunction [63].…”